The present invention relates to a method for preparing 1,4-dihydropyridine-3,5-dicarboxylic acid diesters, and more particularly, it relates to unsymmetrical 1,4-dihydropyridine 3,5-dicarboxylic acid di(nitratoalkyl) esters useful as therapeutic agents for cardiovascular disorders.
In the past, 1,4-dihydropyridine-3,5-dicarboxylic acid di(nitratoalkyl) esters are prepared as shown in the following reaction schemes (U.S. Pat. No. 4,472,411). ##STR2## wherein Y and Z are each a nitratoalkyl group having 2 or 3 carbon atoms.
However, when Y and Z are different, these methods results in the formation of two by-products of symmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid di(nitratoalkyl) esters represented by the following general formulae ##STR3## wherein Y and Z are as defined above. Although the formation of these by-products is in a small amount, since they are very similar in the physical properties to the objective compound of the unsymmetrical 1,4-dihydropyridine derivative, these methods require complicate purification procedure in order to give the objective compound in high purity. Accordingly, these methods are disadvantageous industrially.
On the other hand, there are known the methods for preparing some unsymmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid diesters which comprises the esterification of the corresponding 3,5-dicarboxylic acid monoester with dialkylaminoethyl chloride (Reaction Scheme 3, U.S. Pat. No. 3,996,234), and which comprises the reaction of the corresponding 3,5-dicarboxylic acid monoester with phosphorus pentachloride, followed by the esterification of the resulting acid chloride with dialkylaminoethyl alcohol [Reaction Scheme 4; Chem. Pharm. Bull., 28(9), 2809 (1980)]. However, these methods can not be said to be advantageous industrially since the former method can only be applied to the compound having the substituent at the nitrogen atom of the dihydropyridine ring, and the yield of the latter method is low. ##STR4##
As a result of the earnest studies to resolve the drawbacks of the prior art methods, the present inventors have succeeded in preparing unsymmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid diesters from 1,4-dihydroxypyridine-3,5-dicarboxylic acid monoesters in extremely high purity, and completed the present invention.